Efficacy of Ipilimumab vs FOLFOX in Combination With Nivolumab and Trastuzumab in Patients With Previously Untreated <i>ERBB2</i>-Positive Esophagogastric Adenocarcinoma
Authors: Alexander Stein, Lisa Paschold, Joseph Tintelnot, Eray Goekkurt, Svenja-Sibylla Henkes, Donjete Simnica, Christoph Schultheiss, Edith Willscher, Marcus Bauer, Claudia Wickenhauser, Peter Thuss-Patience, Sylvie Lorenzen, Thomas Ettrich, Jorge Riera-Knorrenschild, Lutz Jacobasch, Albrecht Kretzschmar, Stefan Kubicka, Salah-Eddin Al-Batran, Anke Reinacher-Schick, Daniel Pink, Marianne Sinn, Udo Lindig, Wolfgang Hiegl, Axel Hinke, Susanna Hegewisch-Becker, Mascha Binder
Journal: JAMA Oncology (2022)

<h3>Importance</h3> In metastatic esophagogastric adenocarcinoma (EGA), the addition of programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes in selected patient populations. <h3>Objective</h3> To investigate the efficacy of trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced<i>ERBB2</i>-positive EGA. <h3>Design, Setting, and Participants</h3> This phase 2 multicenter, outpatient, randomized clinical trial with 2 experimental arms compared with historical control individually was conducted between March 2018 and May 2020 across 21 German sites. The reported results are based on a median follow-up of 14.3 months. Patients with previously untreated, metastatic<i>ERBB2</i>-positive (local immunohistochemistry score of 3+ or 2+/in situ hybridization amplification positive) EGA, adequate organ function, and eligibility for immunotherapy were included. Data analysis was performed from June to September 2021. <h3>Interventions</h3> Patients were randomized to trastuzumab and nivolumab (1 mg/kg × 4/240 mg for up to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 mg/kg × 4 for up to 12 weeks) (ipilimumab arm). <h3>Main Outcomes and Measures</h3> The primary end point was survival improvement with a targeted increase of the 12-month overall survival rate from 55% (trastuzumab/chemotherapy—ToGA regimen) to 70% in each arm. <h3>Results</h3> A total of 97 patients were enrolled, and 88 were randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and confirmed<i>ERBB2</i>positivity in 76 patients. The observed overall survival rate at 12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm, respectively, with a higher incidence of autoimmune-related AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy analyses showed strong correlation of early cell-free DNA increase with shorter progression-free and overall survival and emergence of truncating and epitope-loss<i>ERBB2</i>resistance sequence variations with trastuzumab treatment. <h3>Conclusions and Relevance</h3> In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in<i>ERBB2</i>-positive EGA. The ipilimumab arm yielded similar OS compared with the ToGA regimen. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03409848